Fetal Alcohol Syndrome Research Today is a free monthly online journal that collates and summarizes the latest research about Fetal Alcohol Syndrome, including details on pregnancy, birth defects, causes, symptoms, treatment.

Stimulation of the cAMP pathway protects cultured cerebellar granule neurons against alcohol-induced cell death by activating the neuronal nitric oxide synthase (nNOS) gene.

Karaçay B, Li G, Pantazis NJ, Bonthius DJ

Division of Child Neurology, Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242, USA. bahri-karacay@uiowa.edu

Neuronal loss is a key component of fetal alcohol syndrome pathophysiology. Therefore, identification of molecules and signaling pathways that ameliorate alcohol-induced neuronal death is important. We have previously reported that neuronal nitric oxide synthase (nNOS) can protect developing cerebellar granule neurons (CGN) against alcohol-induced death both in vitro and in vivo. However, the upstream signal controlling nNOS expression in CGN is unknown. Activated cAMP response element binding protein (CREB) has been strongly linked to the survival of multiple cell types, including CGN. Furthermore, the promoter of the nNOS gene contains two cAMP response elements (CRE). Using cultures of CGN, we tested the hypothesis that cAMP mediates nNOS activation and the protective effect of nNOS against alcohol-induced cell death. Forskolin, an activator of the cAMP pathway, stimulated expression of a reporter gene under the control of the nNOS promoter, and this stimulation was substantially reduced when the two CREs were mutated. Forskolin increased nNOS mRNA levels several fold, increased production of nitric oxide, and abolished alcohol's toxic effect in wild type CGN. Furthermore, forskolin's protective effect was substantially reduced in CGN cultures genetically deficient for nNOS (from nNOS-/- mice). Delivery of nNOS cDNA using a replication-deficient adenoviral vector into nNOS-/- CGN abolished alcohol-induced neuronal death. In addition, overexpression of nNOS in wild type CGN ameliorated alcohol-induced cell death. These results indicate that the neuroprotective effect of the cAMP pathway is mediated, in part, by the pathway's downstream target, the nNOS gene.

Published 26 March 2007 in Brain Res, 1143: 34-45.
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